Substituted imidazoles



Patented July 16,1946

SUBSTITUTED IMIDAZOLJES Lucas P. Kyrides, Webster Groves, Mo., assignor to Monsanto Chemical Company, St. Louis, Mo.,

a corporation of Delaware No Drawing. Application March 3, 1944, Serial No. 524,929

7 Claims. (Cl. 2.60309) The present invention relates to the production of new therapeutic agents and insecticide toxicants which are substituted lmidazole compounds, and comprises the method of producing the compounds as well as the new products themselves.

According to the present invention, generally stated, new products which are of outstanding value as active agents against micro-organisms are made by preparing substituted imidazoles of the type represented by the formula:

may be located in various positions in the chain.

R1 may be a straight chain alkyl radical such as the methyl, ethyl, propyl, butyl and amyl radicals, or a branched chain alkyl radical such as the isopropyl, tertiary butyl and isoamyl radicals. Likewise, R1 may be an alkenyl radical having from 1 to 5 carbon atoms in its straight or branched chain structure, for example, the propenyl, butenyl and isobutenyl radicals. The water-soluble salts of these compounds may be prepared and are also valuable as active agents against micro-organisms andas insecticide toxicants. For example, the hydrochlorides, hydrobromides and acetates and other salts may be employed:

The new products and their water-soluble salts may be administered orally orparenterally and have been found to be unusually efiective against micro-organisms such as streptococcus in vitro The acyclic hydrocarbon radical and in vivo; The organic and inorganic acid salts may be prepared by dissolving the products in an aqueous solution containing the stoichiometrical equivalent of a suitable acid, such as hydrochloric, hydrobromic, acetic acids and'the like, and the solution may be employed for parenteral administration.= Also, the .acid salts maybe prepared during the synthesis of the imidazole derivative or immediately thereafter and before the product is isolated from the reaction mixture.

The products of the present invention have "also.

been found to possess utility as insecticides and toxicants for insecticide compositions; such as sprays and powders in which the compounds are blended with suitable wetting agents; fillers, s01- vents, adhesives, coating agents; repellents'and other ingredients employed in compounding insecticides.

The products of the present invention may be prepared by reacting ethylene diamine with a molecular'equivalent or less of an acylating agent comprising an aliphaticmonocarboxylic acid hav ing as-its alkyl oralkenyl residue one of the radica'ls described hereinbefore" in the definition of R1 withfrespect to the formula. The acid thus employedwill be composed "of an alkyl oralker'iyl residue offthe proper chain length or with the proper branchedchain components together with a carboxylic acid group, the carbon atom of which is not included in the contemplation of thecha'in length hereinbefore described. In place of the acid, the alkyl e'stensuch as the butyl ester, or desirably the m'ethyl' or ethyl ester, maybe cmployed, or the acyl halide such as the acyl chloride, or the acid anhydride. I

The resulting mono-acyl amino derivative is then condensed with the aid of a suitable mild dehydrating agent, such .as powdered calcium oxide, to form the 2-alkyl (or 2-alkenyl) imidazoline. The derivative thus prepared is then reacted with an alkylating agent having as its alkyl residue one of the residuesdescribed hereinbefore in the definition of R with respect to the formula. The alkylating agent may be an alkyl halide, such as lauryl chloride or tride'c'yl bromide. The derivative thus prepared is then dehydrog'n atedwith the aid of a suitable dehydrogenation catalyst, such as nickel, to form the l-alkyl (or alkenyl)-2-alkyl (or all senyl) imidazole.

In carrying out the preparation of the N-acyl ethylene diamine, it is desirableito employ anhydrous ethylene diamine; However, ethylene diamine that is not substantially anhydrous may be employed. The anhydrous material facilitates the attainment of somewhat higher yields.

The following examplesjillustrate the process of the present invention and the compounds resulting therefrom. These examples arewbe construed as merely illustrating and not as limiting the scope of the present invention.

A mixture, 'oi264 grams of anhydrous ethyl acetate (3 moles) and 540 grams of ethylene diamine (9 moles) was heated in an autoclave at 100-110 C. for 36 hours. A pressure of about 20 pounds was developed. The mixture was transferred to a still and the ethanoland excess ethylene diamine were distilled ofi at about-100' 7 ing to 90100 C., the mixture was extracted with three 500 cc. portions of alcohol. The alcohol was removed from the extract by distillation and the residue was distilled at atmospheric pressure. 13. P. 195198 0.- Yield of2-methyl-4,5-dihydroimidazole, 88%. I

A mixture of 100.8 grams of 2-Inethyl-4,5-dihydroimidazole, 123.0 grams of n-dodecyl chloride (0.6 mole) and290 cc. of xylene was refluxed at 148 C. for 16 hours and then cooled to 25 C.

IA- solutionof 50 grams of 50% sodium hydroxide solutionv in .33 cc. of water was added with agitation; The mixture was filtered and the xylene layer was separated from the filtrate. After 1'6.- movalof the xylene underreduced pressure, the residue was distilled, B." P. 177-184 C./ 6 min. The yie1d Was60.7f g raI hs 01 40.2%, tialdulat ed on n-dodecyl chloride charged. The. preeue': as

'droimidazole. I 'In place of n-dodecyl chloride. n-dodecyl bro- 'mide'may'be employed. l

' For the. dehydrogenation of 1-n-dedecy1-2- methyl-4,5-dihydroimidazole, a nickel catalyst was prepared by heating nickel formate in a mineral oil until decomposition of the formate occured. The nickel catalyst may be prepared by other methods, for'example, the method disclosed in U. S. Patent 1,378,736, issued May 17, 1921, to Ellis. Other suitable dehydrogenation catalysts, such as Raney nickel catalysts, may be employed. A mixture of.3.2 grams .ofjhe catalyst thus prepared and 60.7 grams of l-n-dodecyl-2-methyl-4,5-dihydroimidazole was heated with agitation to 225-235 C. until hydrogen was no. longer evolved. The reaction mixture was cooled to 125 C. and gram of the nickel catalyst was added. Heating was resumed and continued until ,the evolution of hydrogen ceased.

The reaction mixture was then distilled in vacuo'. The'distilled product was 1-n-dodecyl-2-methylimidazole.

e Example 2 0% 07cm .j.

r A mix'tu re of150.4 grams (0.6 mole) of 2i-meth'yl 4,5-dihydroimidazole, prepared according to'i'the method 'ofExample 1, 52.8 grams "(0.3 mole) of decyl chloride and 100 cc. of benzene was refluxed for 7 hours and cooled to room temperature. The mixture was treated with 150 cc. of water and 24 grams of sodium hydroxide solution with agitation and filtered. The benzene layer of the filtrate was separated and distilled to remove the benzene. The residue was distilled at reduced pressure to recover the product. B. P. 151-155 C./6 mm. Yield of 1-n-decyl-2-methyl-4,5-dihydroimidazole, 41.3%. The material assayed 99.8%. This material was dehydrogenated according to the method of Example 1. Yield of 1-n-decy1-2-methyl-imidazole, 90.5% of theory. B. P. 153-160 C./5.5 mm.

Example 3 1-n-Tetradecyl-2-methyl-imidazole i CHN-CH -(OH2)1a-CHa on C-OHs A mixture of 60.7 grams of 2-methyl-4,5-dihydroimidazole prepared according to the method ofExample 1, 83 grams of tetradecyl chloride and cc. of xylene was refluxed 18 hours at C.

The mixture was cooled to room temperature and diluted with 125 cc of water. To this mixture, 27.5 grams of 50% sodium hydroxide was added with agitation. The resulting mixture was-filtered and the xylene layerwas separated and distilled to remove the xylene. The residue was distilled at reduced pressure to recover the prod- B..P.j-193 C./6 mm. .Yield of 1-ntetradecyl-2-methy1-4,5-dihydroimidazole, j 34%. The material assayed 97.4%. This material was dehydrogenated according to the method of Example 1. The product was l-n-tetradecyl-2- methyl-imidazole. B. P. 187-199 C./5.5 mm.

mixture of 427.7 gramsof anhydrous methyl caproateand 592 grams of anhydrous ethylene diamine was reacted according to the method of Example 1. The N-caproyl-ethylene diamine obtained was condensed with the aid of anhydrous calcium oxide according to the method of Example 1. The product was identified as 2- amyl-4,5 -dihydroimidazole. B. P. l50-l57 C./34 mm. The yield of this material was 56.8%, based on methyl caproate. The M. P. of the material was 53-54:.6" C. V

. Amixture of 168 grams imidazole, 123 grams of n-dodecyl chloride and 200 ,cc. of xylene was reactedaccording to the method ofExampleLand thejresulting' reaction mixture was treated with 50 grams of 50% sodium hydroxide solution in 300 cc. of Water. After fil tration, removalofjxylene from the non-aqueous layerand distillation of the residue, the material recovered was identified as l-n-dodecyl-2-namyl-4,5-dihydroimidazole. This material was 'dehydrogenated according to the method of Example I 1. The product was. l-n-dodecyl 2amyleem tuna may blpreparea by reeetilsee mixture or- 101 grams or 2-n'iethyl 4',5-dihydro- "imidazole repared according to Example 1,144 7 4,5-dihydroimidazole according to the method of Example 1.

Example 7 l-n-Dodecyl-Zcthyl-imidazole E1HNCH2- (CH2) 1o- CH3 CH o-om-cm This compound may be prepared by reacting a mixture of anhydrous methyl propionate and an excess of anhydrous ethylene diamine according to the method of Example 1 to form N- pro'pionyl ethylene diamine. This product may be condensed with calcium oxide according to the method of Example 1 to form 2-ethyl-4,5-dihydroimidazole. This latter product'may be reacted with n-dodecyl chloride according to the method of Example 2 to form 1-n-dodecyl-2-ethyl-4,5-dihydroimidazole. This material may the lqe d hydrogenated according to themethod of'Example 1 to form 1-n-dodecyl-2-ethyl imidaaole.

' Example 8 x l-n-Dodecy1-2-propenyl-imidazole C H-N-CH2- (QH2)m-CHa I I OH GCH=CH-CHB This compound may beprepared by reacting a mixture of anhydrous methyl crotonate and an excess of anhydrous ethylene diamine according to'the method of Example 1' to produceN crotonyl ethylene diamine, This product may be condensed with calcium oxide according to the method of Example 1 to produce 2-propenyl-4,5'-

diliydroimidaz'ole'. This latter product may then be reacted with n-dodecylchloride according to the method of Example 1 with the resultant production of l-n-,dodecyl 2-'propenyl-4,5-dihydroimidazole. This material may then be dehydrogenated according to the method of Example 1 to form 1-n-dodecyl-2-propenyl-imidazole.

Example 9 l-n-Dodecyl-2-isopropyl-imidazo1e CH-N-CHz- (CH2)10- CH: l CH3 -oH--o N CH3 Thi compound may be prepared by reactin a mixture of anhydrous methyl isobutyrate and an excess of anhydrous ethylene diamine according to the method of Example 1. The resulting product, N-isobutyryl ethylene diamine, is condensed with calcium oxide according to the method'of t "6' "Example '1 to produce 2-isopropyl-4 5-dihydroimidazole. This latter'may then .be reacted with n-dodecyl chloride according to the method of Example 2' with the resultant production of l-ndodecyl- 2-isopropyl-4,5-dihydroimidazole. This material may then be deh'ydrogenated according to the method of Example 1 to form l-n-dodecyl- 2-isopropyl-imidazole.

Example 10 l- Dodecyl-z-isobutenyl-imidazole V OHN;-CH:--(CH2) 10- CH: H: CH N CHa r.

This compound may be prepareid by reacting a mixture of anhydrous methyl dimethacrylate and an excess of anhydrous ethylene diamine according to the method of Example 1. The product recovered from the reaction mixture, N-dimethacroyl ethylene diamine, is then condensed with calcium oxide with the resultant production of 2-isobutenyl- 4,5-dihydroimidazole. This latter product may then be reacted with n-dodecyl chloride according to the method of Example 2 to form l-n-dodecyl-2-is0butenyl-4,5-dihydroimidazole. This material may then be dehydrogenated according to the method of Example 1 to form 1-dodecyl-2-isobutenyl-imidazole.

This compound may be prepared by reacting a imidazole, prepared as in Example 8 according to the method of Example 1, 138 grams of 12-tetradecenyl chloride and 200 cc. of xylene according to the method of Example 1, and treating resulting reaction mixture as in Example 1 to recover the product. v Example 13 1-n-Decy1-2-amy1-imidazole CE C-CHa-(CHzh-CHa A mixture of 2 mols of 2-amyl-4,5-dihydroimidazole, prepared according to the method of Example 4, and one mol of n-decyl chloride was heated at 144-150 C. for 15 hours. The reaction product was diluted with Water, treated with a 5% excess of sodium hydroxide, and extracting to the method of Example 1.

'7 ediwith'. n-butyl alcohol. The butyl alcohol and some :unreacted 2 amyl 4,5 dihydroimidazole Were removed from the extract by distillation. The residue was distilled, B. P. 143-174.5/3.5 mm., and thereafter redistilled, B. P. 157-17073 mm. This material was dehydrogenated accord- The product was 1-n-decyl-2-amyl-imidazole. Yield 93.8%; B. P. 149-176" O./3.5 mm.

The present invention is a continuation-in-part of my copending application S. N; 498,583, filed August 13, 1943, which discloses the 4,5-dihydroimidazole derivatives from which the novel therapeutic agents of the present invention may be 7 derived as explained hereinbefore.

I claim: 1. A compound of the group consisting of. substituted im idazoles'of the formula type:

in which R represents an acyclic hydrocarbon radical having from 10 to 16 carbon atoms in its structure and Rrrepresents an acyclic hydrocarbon radical having from 1 to carbon atoms in its structure andacid salts thereof, preparedfor useas therapeutic agents. V 2. Substituted imidazoles of the formula type:

. 1(| |;H N RI 19 rew in which Rrepresents a straight chain alkyl radical having from to 16'carbon atoms in its structure and R1 represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure, prepared for use as therapeutic agents.v I

3. .The 1-n-decyl-2-methyl-imidazole of the formula: we v j V uH NoH2-(c11i)tom c-on,

prepared for use as a therapeutic agent.

4. The 1-n-dodecyl-2-methyl-imidazole of the formula: V

-CH N.CH2-(OH2)in- CH3 on O-CHa 7 prepared for use as a therapeutic agent.

' 5. The 1-n+tetradecyl-2-methyl-imidazole of theformula:

i I GH NCHz-(CH2)12-CH:

0H" CHz I a N prepared for use as a therapeutic agent.

6. A process for preparing compounds 'ofthe formula type: v c c ,CH-i -R in which R represents an acyclic hydrocarbon radical having from 10' to 16 carbon atoms in its structure and R1 represents an acyclic hydrocarbon'radical having from 1 to 5 carbon atoms in its structure, said process comprising reacting v ethylene diamine with an alkyl ester of a monocarboxylic acid in which a carboxylic group' is attached to a radical selected from the group of radicals defined hereinbefor as R1, heating the ethylene diamine derivative thus formed in the presence of a mild dehydrating agent, reacting the derivative thus formed with an alkyl halide having an alkyl radical selected from the group of radicals defined hereinbefore as R, heating the derivative thus formed with a dehydrogenation catalyst and distilling oif the dehydrogenation product;

J 7. A process for preparing compounds of the formula type: J

in 'whichR represents a straight chain alkyl i radicalhaving from 10 to '16 carbon atoms in its structure and R1 represents anacyclic hydrocarbon radical having from 1 to 5 carbon atoms in its structure, said process comprising reacting ethylene diamine with an alkyl ester of a monocarboxylic acid in which a carboxylic group is attached to a radical selected from the group of radicals defined hereinbefore as R1, heating the ethylene diamin derivative thus formed in the presence of a mild dehydrating agent, reacting the derivative thus formed with an alkyl halide having an alkyl radical selected from the group a of radicals defined hereinbefore as R, heating the 

